Estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of a variety of biological effects through the interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and Estrone. ER has two subtypes, estrogen receptor α (ERα, ESR1 and NR3A) and estrogen receptor β (ERβ, ESR2 and NR3b). Estrogen receptor α and estrogen receptor β are members of the steroid hormone receptor, which is a member of the nuclear receptor family. Similar to the mechanism of the nuclear receptor, ERα is composed of six functional domains (named A to F), which is a ligand-activated transcription factor. After binding to a specific ligand including endogenous estrogens 1713 Estradiol (E2), ERα binds to a genomic sequence into a complex, that is, an estrogen receptor responsive element and a co-regulatory factor bind together to regulate the transcription of the target gene. The ERα gene is located at 6q25.1, encoding the 595A protein, resulting in different subtypes depending on the cleavage sites and the transcription initiation points. In addition to the DNA binding domain (domain C) and the ligand binding domain (E domain), the receptor also includes the N-terminal (A/B domain), the hinge region (D domain which connects the C and E domains) and the C-terminal (F domain). The ERα and ERβ are consistent in C and E domains and have a low consistency in A/B, D and F domains. Both receptors are related to the regulation and growth of the female genital tract and play an important role in the central nervous system, cardiovascular system and bone metabolism. The binding of estrogen and receptor can lead to a variety of cell changes, the regulatory mechanism thereof can be divided into two ways: genome and non-genomic pathways. ER-mediated genomic pathway includes estrogen receptor dimer formation, binding to ERE in the estrogen-regulated gene promoter, mediating aggregation of other regulatory proteins into the promoter, and ultimately leads to an increase or decrease in the mRNA level of the gene. In Estrogen-mediated non-genomic pathway, estrogen reacts with estrogen-binding proteins that are present in or adjacent to the cell membrane of ERs, and even the cell membrane without ERs. The cell responses caused by estrogen through non-genomic pathway, can increase intracellular calcium and NO levels, as well as a variety of intracellular kinase activation, including MAPK, PI3K, PKA and PKC, causing nER phosphorylation and activation.
About 70% of patients who suffer from breast cancer express ER and/or progesterone receptors, indicating that the growth of this tumor cells is hormone-dependent, and the growth of other tumors such as ovarian cancer and endometrial cancer is also dependent on ERα. The treatment of these diseases can be done by inhibiting ER signaling through a variety of ways, including antagonism the binding of ligand to ER, antagonism or down-regulation of ERα, blocking estrogen synthesis, and the like. At the same time the ERα and ERβ are expressed in the endocrine tumors such as adrenal cortical tumors, pancreatic cancer, prostate cancer and thyroid cancer, gastrointestinal system tumors such as colon cancer, esophageal cancer, liver cancer and pancreatic cancer, and lung cancer. Although the above-mentioned treatment has played a role in ER-positive cancer patients, it also leads to drug resistance. Recently, it has been reported that ESR1 mutations may be one of the causes of resistance to metastatic ER-positive breast cancer patients (Toy et al., Nat. Genetic 2013, 45:1439-1445; Li, S. et al Cell Rep. 4, 1116-1130 (2013)). However, in the possible resistance mechanisms, the growth of tumor shows ER dependent activity, and therefore the mechanism by which ERα is selectively reduced provides a better way to block ERα activity mediated early, metastatic and drug resistant cancers.
It has been disclosed that a number of drugs that can be used as selective estrogen receptor downregulator (degrader) (SERD) by now, including GDC-0810 and GDC-0927 from Genentech in clinical phase II and Clinical phase I respectively; AZD-9496 from AstraZeneca in clinical phase I, and a series of SERD patent applications, including WO2011156518, WO2012037410, WO2015082990 and the like. However, there is still a need to study and develop new estrogen receptor α downregulators.